Islet cell transplantation for patients with type I autoimmune diabetes has the potential to cure diabetes and protect against its debilitating complications. Substantial obstacles in the field of islet transplantation slowed its clinical implementation for decades. The recent breakthrough with the first series of successful islet transplantation in Edmonton Canada reestablished transplantation of islets of Langerhans as a viable therapeutic option for the cure of type I diabetes. The clinical applicability and wide spread use of this therapy is hampered by two major obstacles:(i) the requirement for a high number of islets derived from at least two pancreata to achieve euglycemia, and (ii) the need for intensive immunosuppression that cannot be given to the pediatric population. The causes underlying the failure of islet transplantation are multifactorial including (i) primary non-function, (ii) allograft rejection and (iii) recurrence of autoimmunity. Regardless of the cause, islets are ultimately destroyed by apoptosis. Efforts directed at engineering "death-defying" islets able to resist immune and non-immune injuries may offer a solution by reducing the number of islets required and allowing the use of milder immunosuppression. Our work is focused on defining "protective" candidates for the genetic engineering of islets. Our preliminary data reveals that A20 is part of the physiological response of islets to injury. Expression of A20 in islets protects from cytokine and Fas/FasL mediated apoptosis and exerts a potent anti-inflammatory effect via blockade of NF-?B. We have already shown that overexpression of A20 in islets overcomes the first hurdle facing successful transplantation namely, primary non-function. We aim to determine whether genetic engineering with the cytoprotective gene A20, will protect islets from allograft rejection (C57BL/6 to diabetic BALB/c) and recurrent autoimmunity (NOD-scid to diabetic NOD). Finally, we will determine whether A20 will enable successful transplantation of allogeneic islets into autoimmune recipients (C57BL/6 into diabetic NOD). Gene transfer will be performed using both recombinant adenoviruses (rAd.) and recombinant associated adenoviruses (rAAV) that have both been shown to efficiently transduce islets without major toxicity or impairment of function. It is our belief that overexpression of the cytoprotective gene A20 will protect islets from the allo and autoimmune insults. This will overcome the requirement for high numbers of islets and the need for intensive immunosuppression. Beneficial results would pave the way for pre-clinical (primates) and clinical applications.